Chemotherapy can provide a therapeutic benefit in many cancer subjects, but it often ultimately fails to cure the disease because cancer cells can become resistant to the chemotherapeutic agent. To overcome these limitations additional antineoplastic strategies are needed, such as the use of potentiating agents that restore or amplify the effect of antitumor agents. Such amplification agents could also permit lower doses of cytotoxic drugs to be used, which could help minimize unwanted side-effects of the cytotoxic drugs.
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) acts in the Topoisomerase I (TopI) pathway to counteract the anticancer activity of TopI inhibitors and promote tumor resistance of chemotherapeutic drugs. In particular, Tdp1 is a DNA repair enzyme that is involved in the repair of DNA lesions that are created when the activity of TopI is inhibited, for example by TopI inhibitors that have anticancer activity. Tdp1 is an enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of TopI. For this reason, Tdp1 has been implicated in the repair of irreversible TopI-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of TopI in that it seemingly counteracts the effects of TopI inhibitors, such as camptothecin. Thus, by reducing the repair of TopI-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of TopI inhibitors.